Drug resistance proteins LRP, Pgp, MRP1, MRP3 and MRP5 in ovarian cancer patients

Czech version

Authors: I. Sedláková ¹; J. Laco ²; J. Tošner ¹; J. Špaček ¹; Eva Čermáková ³
Authors‘ workplace: Porodnická a gynekologická klinika LF UK a FN, Hradec Králové, přednosta doc. MUDr. J. Špaček, Ph. D., IFEPAG ¹; Fingerlandův ústav patologie LF UK a FN, Hradec Králové, přednosta prof. MUDr. A. Ryška, Ph. D. ²; Ústav lékařské biofyziky LF UK, Hradec Králové, přednosta doc. MUDr. J. Hanuš, CSc. ³
Published in: Ceska Gynekol 2013; 78(6): 545-553
Category: Original Article

Overview

Objective:
To evaluate the correlation of drug resistance proteins LRP (Lung Resistance Protein), Pgp (P-glycoprotein), MRP1 (Multidrug Related Protein, Multidrug Resistance–Associated Protein), MRP3 a MRP5 with clinical – pathological factors and to find the clinical outcome of these data in ovarian cancer patients.

Design:
Prospective study.

Setting:
Department of Obstetrics and Gynecology, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Kralove.

Methods:
111 patients with epithelial ovarian cancer who underwent primary surgery from 2006–2010 had specimens stained with imunohistochemistry for LRP, Pgp, MRP1, MRP3, MRP5.

Results:
The histological subtype of epithelial ovarian cancer correlated to the LRP, Pgp, MRP1 and MRP3 expression. Patients with late ovarian cancer had a higher MRP1 compared to early stage ovarian cancer (I+II 71.6% (CI 60–100), III+IV 83.6% (CI 100–100),p = 0.03). Correlation of MRP1 with grading was found(G1 60.83% (CI 10–100), G2 36.80% (CI 20–100),G3 88.87% (CI 100–100), p = 0.039). Patients with high Pgp, MRP1 and MRP3 expression had significantly shorter progression-free survival. (Kaplan-Meier test – PFS, Pgp < 85% Med PFS 23 months (CI 8–37) vs > 85% Med PFS 11 months (CI 7–17), p = 0.054), (MRP1 < 85% Med PFS 33 months (CI 11–49) vs > 85% Med PFS 11 months(CI 7–16), p = 0.046).

Conclusion:
We found clinical significance of LRP, Pgp, MRP1 and MRP3 expression in ovarian cancer patients. MRP5 expression did not correlate with neither histo-pathological parameters nor progression free survival. MRP1 have some additional predictive and prognostic value for the clinical outcome of patients with ovarian carcinoma.

Keywords:
ovarian carcinoma – LRP – Pgp/ABCB1 – MRP1/ABCC1 – MRP3/ABCC3 – MRP5/ABCC5 – drug resistance

Sources

1. Arao, S., Suwa, H., Mandai, M., et al. Expression of multidrug resistance gene and localization of P-glycoprotein in human primary ovarian cancer. Cancer Res, 1995, vol. 54, p. 1355–1359.

2. Arts, HJ., Katsaros, D., de Vries, FG., et al. Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. Clin Cancer Res, 1999, 5, p. 2798–2805.

3. Borst, P., Evers, P., Kool, M., Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst, 2000, 92, p. 1295–1302.

4. Cibula, D., Petruželka, L., a kol. Onkogynekologie, 1. vyd. Praha: Grada Publishing, 2009.

5. Codegoni, AM., Broggini, M., Pitelli, MR., et al. Expression of genes of potential importance in the response to chemotherapy and DNA repair in patients with ovarian cancer. Gynecol Oncol, 1997, 65, p. 130–137.

6. Fruehauf, PJ., Alberts, DS. In vitro drug resistance versus chemosensitivity: two sides of different coins. J Clin Oncol, 2005, 23, p. 3641–3643.

7. Glavinas, H., Krajcsi, P., Cserepes, J., et al. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv, 2004, 1, p. 27.

8. Goff, AB., Paley, JP., Greer, EB., Grown, MA. Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma. Gynecol Oncol, 2001, 81, p. 18–24.

9. Gottesman, MM., Fojo, T., Bates, SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer, 2002, 2, p. 48–58.

10. Holzmayer, TA., Hilsenbeck, S., Von Hoff DD., Roninson, IB. Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst, 1992, 84, p. 1486–1491.

11. Charpin, C., Vielh, P., Duffaud, F. et al. Quantitative immunocytochemical assays of P-glycoprotein in breast carcinomas: correlation to messenger RNA expression and to immunohistochemical prognostic indicators. J Natl Cancer Inst, 1994, 86, p. 1539–1545.

12. Ikeda, K., Sakai, K., Yamamoti, R., et al. Multivariate analysis for prognostic significance of histologic sybtype, GST-pi, MDR-1, and p-53 in stages II–IV ovarian cancer. Int J Gynecol Cancer, 2003, 13, p. 776–784.

13. Izquierdo, MA., Schoemaker, RH., Flens, MJ., et al. Over-lapping phenotypes of multidrug resistance among panels of human cancer-cell lines. Int J Cancer, 1996, 65, p. 230–237.

14. Izquierdo, M.A., van der Zee, AG., Vermorken, JB., et al. Drug resistance-associated marker LRP for prediction of response to chemotherapy and prognosis in advanced ovarian carcinoma.J Natl Cancer Inst, 1995, 87, p. 1230–1237.

15. Kuwano, M., Uchiumi, T., Hayakawa, H., et al. The basic and clinical implications of ABC transporters, Y-box-binding protein-1 and angiogenesis-related factors in human malignancies. Cancer Sci, 2003, 94, p. 9–14.

16. Materna, V., Pleger, J., Hoffmann, U., Lage, H. RNA--expression of MDR1/P-glycoprotein, DNA-topoisomerase I, and MRP2 in ovarian carcinoma patients: correlation with chemotherapeutic response. Gynecol Oncol, 2004, 94, p. 152–160.

17. Nosková, V., Hajdúch, M., Mihál, V., Cwiertka, K. Mechanismy mnohočetné lékové rezistence a jejich význam pro klinickou praxi. Klin Onkol, 2000, 13, s. 4–9.

18. Rubin, SC., Finstad, CL., Hoskins, WJ., et al. Expression of P-glycoprotein in epithelial ovarian cancer: evaluation as a marker of multidrug resistance. Am J Obstet Gynecol, 1990, 163, p. 69–73.

19. Sedláková, I., Laco, J., Tošner, J., et al. Proteiny rezistence a chemorezistence u pacientek s karcinomem ovaria. Klin Onkol, 2012, 25, p. 457–463.

20. Scheffer, GL., Wijngaard, PL., Flens, MJ., et al. The drug resistance related protein LRP is the human major vault protein. Nat Med, 1995, 1, p. 578–582.

21. Schinkel, AH. P-Glycoprotein, a gatekeeper in the blood-brain barier. Adv Drug Deliv Rev, 1999, 36, p. 179–194.

22. Václavíková, R., Hubáčková, M., Kubala, E., et al. Exprese genu mnohočetné lékové rezistence 1 (MDR1) a její význam v rozvoji a terapii karcinomu prsu. Klin Onkol, 2007, 3, p. 253–259.

23. Yakirevich, E., Sabo, E., Naroditsky, I., et al. Multidrug resistance-related phenotype and apoptosis-related protein expression in ovarian serous carcinomas. Gynecol Oncol, 2006, 100, p. 152–159.